Process for preparation of substituted 2-amino-5-(5-(heterocyclemethyl)pyridin-2-yloxy)benzoic acid

A process of preparing a compound of formula (I) or a salt thereof,

• wherein
• R1 is a heterocycle selected from the group consisting of:
• R2 is selected from H, F, Cl, CN, CF3, (C1-6)alkyl, (C3-12)cycloalkyl and —O—(C1-6)alkyl;
• R3 is selected from H, F, Cl, CN, (C1-6)alkyl, —OH, —O—(C1-6)alkyl, S—(C1-6)alkyl, —NH2, —NH(C1-6)alkyl, —NH(C3-12)cycloalkyl, —N((C1-6)alkyl (C3-12)cycloalkyl) and —N((C1-6)alkyl)2;
• R4 and R5 are each independently selected from H, (C1-6)alkyl, (C3-12)cycloalkyl and oxo (C(═O));
• R6, R7, and R8 are each independently selected from H, F, Cl, (C1-6)alkyl, and (C3-12)cycloalkyl;
• R9 is selected from H, F, Cl, (C1-6)alkyl, and (C3-12)cycloalkyl;
• R10 is selected from H, (C1-6)alkyl, and (C3-12)cycloalkyl;
• wherein each of R1 to R10 is optionally substituted by one or more substituents selected from H, F, Cl, CF3, OXO, (C1-6)alkyl, (C3-12)cycloalkyl, (C1-6)alkyl(C3-12)cycloalkyl, —OH, —SH, —O(C1-6)alkyl, —S(C1-6)alkyl, —NH2, —NH(C1-6)alkyl and aryl;
• comprising:
• Step A:
• converting a compound of formula (II) to a compound of formula (III) according to reaction scheme 1:
• wherein the compound of Formula (II) is first reacted with methylsulfonyl chloride in the presence of a suitable solvent and at a suitable reaction temperature;
• upon quenching of the reaction and partially or completely removal of the solvent, the resulting mesylate intermediate is reacted with an optionally-brominated R1 in the presence of a suitable base, a suitable solvent and at a suitable reaction temperature to provide the compound of formula (III) wherein m is an integer from 0 to 3 and R11 is a halo;
• Step B:
• converting the compound of formula (III) to a compound of formula (V) according to reaction scheme 2:
• wherein the compound of formula (III) is reacted with a compound of formula (IV) or a salt thereof in the presence of a suitable base, a suitable solvent and at a suitable reaction temperature to provide the compound of formula (V);
• and
• Step C:
• converting the compound for formula (V) to a compound of formula (I) according to reaction scheme 3:
• wherein the compound of formula (V) is hydrogenated in the presence of a suitable catalyst, a suitable solvent and at a suitable reaction temperature to provide a compound of formula (I).